Project Summary Despite the available antiviral drugs and vaccines against seasonal strains, influenza virus causes widespread infection leading to over 35,000 deaths in the United States annually. While clearance of influenza-infected cells is primarily mediated by cytotoxic CD8+ T cells, the now well-established dependency of anti-viral host responses on both innate and adaptive immune compartments suggests that harnessing the innate immunity might form a basis for the development of effective vaccines and novel therapeutic approaches. Although recruitment of innate immune cells to the sites of infectious injury is a hallmark of protective early immune responses during influenza infection, they also cause tissue damage. Thus, a prolong innate immune response and/or delayed resolution has long been believed to be detrimental. However, it is currently not known how apoptotic immune cells are removed within inflamed tissues ? a process fundamental to our understanding and manipulation of inflammatory diseases. Despite recent advances in studies concerning phagocytic removal of apoptotic cells, the visualization of the dynamic cell clearance process in vivo has been extremely challenging. Here we established a novel intravital multi-photon microscopy (IV-MPM) system to address critical knowledge gaps regarding the function and fate of innate immune cells during the influenza infection, and their roles in anti-viral immune responses. With this approach in a mouse influenza infection model, we identified novel interactions between neutrophil and monocyte-derived phagocyte that can actively promote the anti-viral T cell functions in the infected airway. We will (1) determine the mechanism of in situ neutrophil efferocytosis during resolution and (2) investigate how the resolution of innate immune responses regulates T cell effector functions. Given the importance of dynamic immune-modulatory properties during viral infections, elucidating the relationship between innate immunity and effector T cell interactions at the site of infection is critical for deciphering the basis of productive and nonproductive adaptive immune responses and for advancing our capacity to develop new universal vaccines that rely on such cell mediated responses.